It is clear that an adult rat can generate coordinated, weight-supported hindlimb stepping after a complete mid- thoracic transection of the spinal cord when one or more interventions are applied, e.g., step training, pharmacological modulation, and/or epidural stimulation of the lumbosacral spinal cord. While conducting a series of studies, we and others have observed a significant level of rostrocaudal heterogeneity along the lumbosacral spinal cord, as demonstrated physiologically, biochemically, and behaviorally. Specifically, there are unique features of the induced stepping that are dependent on the spinal cord segment stimulated, the type of serotonergic receptors that are activated pharmacologically, and in the anatomical location of those neurons that participate in the generation of spinal locomotion. The present proposal is designed to identify the origin of this rostrocaudal heterogeneity in stepping characteristics that can be attributed to principally 5-HT2A/C and 5-HT1/7 receptors in adult, complete spinal rats. We will determine the degree to which each of these receptor subtypes can contribute to improved stepping, how they uniquely modulate the activation patterns of specific flexor and extensor muscles, and the consequential effects on the kinematics of the hindlimbs. In addition, we will determine how this spinal cord segmental heterogeneity changes in the weeks after a complete spinal injury, with and without robotically controlled step training, and how the capability to induce polysynaptic reflexes relates to the success in the recovery of locomotor ability. These studies also will generate the data needed to further the development of a new electrode array to be used to stimulate specific sites on the spinal cord epidurally and to demonstrate the potential role of this new electrode array technology in improving stepping ability after a spinal cord injury. In effect, these studies will provide the fundamental data needed to determine the feasibility of developing a clinical intervention consisting of epidural stimulation using an electrode array in combination with pharmacological modulation and motor training to enable severely injured individuals to regain weight-bearing capability. PUBLIC HEALTH RELEVANCE The proposed studies will generate the data needed 1) to further the development of an electrode array to be used to stimulate the spinal cord, and 2) to demonstrate the potential of using stimulation of specific regions of the spinal cord through the array for improving stepping ability after a spinal cord injury. Specifically, these studies will demonstrate the feasibility of developing a clinical intervention consisting of stimulation of the spinal cord (via the electrode array placed on the surface of the spinal cord) in combination with pharmacological modulation (administration of drugs that enhance the responsiveness of the spinal cord) and motor training (stepping on a treadmill) to enable severely spinal cord injured individuals to regain weight-bearing standing and stepping capabilities.